Molecular control of the lymphocyte death timer

When stimulated, individual lymphocytes program times for division and death that are inherited within families, revealing a common timing mechanism transmitted over generations. Here we describe a threshold-based mechanism for the time to die. By comparing protein levels in control and apoptosis disabled cells, we show that death can be predicted by a cooperating ensemble of BCL-2 family proteins falling below a critical threshold. Single cell measurements predict the time of death with a simple formula, where an additional inhibition factor explains accelerated death induced by BH3 mimetic compounds. Thus, we identify the death timer as a protein-threshold device that underlies signal integration machinery. Together these results reveal that predicting lymphocyte behavior at single cell level, in complex environments, is possible with modular multiscale models that incorporate timers and heritability features of critical proteins. ### Competing Interest Statement The Walter and Eliza Hall Institute of Medical Research receives milestone and royalty payments related to venetoclax. Employees are entitled to receive benefits related to these payments: C.E.T and D.H.D.G report receiving benefits. D.H.D.G has received research funding from Servier.